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Littérature scientifique sur le sujet « Daclatasvir, NS5A inhibitor »

Auteur : Grafiati

Publié le 9 mars 2023

Mis à jour le 10 mars 2023

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Articles de revues sur le sujet "Daclatasvir, NS5A inhibitor"

Gottwein, Judith M., Sanne B. Jensen, Yi-Ping Li, Lubna Ghanem, Troels K. H. Scheel, Stéphanie B. N. Serre, Lotte Mikkelsen et Jens Bukh. « Combination Treatment with Hepatitis C Virus Protease and NS5A Inhibitors Is Effective against Recombinant Genotype 1a, 2a, and 3a Viruses ». Antimicrobial Agents and Chemotherapy 57, n^o 3 (28 décembre 2012) : 1291–303. http://dx.doi.org/10.1128/aac.02164-12.

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ABSTRACTWith the development of directly acting antivirals, hepatitis C virus (HCV) therapy entered a new era. However, rapid selection of resistance mutations necessitates combination therapy. To study combination therapy in infectious culture systems, we aimed at developing HCV semi-full-length (semi-FL) recombinants relying only on the JFH1 NS3 helicase, NS5B, and the 3′ untranslated region. With identified adaptive mutations, semi-FL recombinants of genotypes(isolates) 1a(TN) and 3a(S52) produced supernatant infectivity titers of ∼4 log10focus-forming units/ml in Huh7.5 cells. Genotype 1a(TN) adaptive mutations allowed generation of 1a(H77) semi-FL virus. Concentration-response profiles revealed the higher efficacy of the NS3 protease inhibitor asunaprevir (BMS-650032) and the NS5A inhibitor daclatasvir (BMS-790052) against 1a(TN and H77) than 3a(S52) viruses. Asunaprevir had intermediate efficacy against previously developed 2a recombinants J6/JFH1 and J6cc. Daclatasvir had intermediate efficacy against J6/JFH1, while low sensitivity was confirmed against J6cc. Using a cross-titration scheme, infected cultures were treated until viral escape or on-treatment virologic suppression occurred. Compared to single-drug treatment, combination treatment with relatively low concentrations of asunaprevir and daclatasvir suppressed infection with all five recombinants. Escaped viruses primarily had substitutions at amino acids in the NS3 protease and NS5A domain I reported to be genotype 1 resistance mutations. Inhibitors showed synergism at drug concentrations reportedin vivo. In summary, semi-FL HCV recombinants, including the most advanced reported genotype 3a infectious culture system, permitted genotype-specific analysis of combination treatment in the context of the complete viral life cycle. Despite differential sensitivity to lead compound NS3 protease and NS5A inhibitors, genotype 1a, 2a, and 3a viruses were suppressed by combination treatment with relatively low concentrations.

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Pelosi, Lenore A., Stacey Voss, Mengping Liu, Min Gao et Julie A. Lemm. « Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir ». Antimicrobial Agents and Chemotherapy 56, n^o 10 (30 juillet 2012) : 5230–39. http://dx.doi.org/10.1128/aac.01209-12.

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ABSTRACTThree hepatitis C virus (HCV) inhibitors, asunaprevir (ASV; BMS-650032), daclatasvir (DCV; BMS-790052), and BMS-791325, each targeting a different nonstructural protein of the virus (NS3, NS5A, and NS5B, respectively), have independently demonstrated encouraging preclinical profiles and are currently undergoing clinical evaluation. Since drug-resistant variants have rapidly developed in response to monotherapy with almost all direct-acting antiviral agents (DAAs) for HCV, the need for combination therapies to effectively eradicate the virus from infected patients is clear. These studies demonstrated the additive-synergistic effects on replicon inhibition and clearance of combining NS3 protease or NS5B RNA polymerase inhibitors with the first-in-class, NS5A replication complex inhibitor daclatasvir (DCV) and reveal new resistance pathways for combinations of two small-molecule inhibitors that differ from those that develop during monotherapy. The results suggest that under a specific selective pressure, a balance must be reached in the fitness costs of substitutions in one target gene when substitutions are also present in another target gene. Further synergies and additional novel resistance substitutions were observed during triple-combination treatment relative to dual-drug therapy, indicating that, in combination, HCV inhibitors can exert cross-target influences on resistance development. Enhanced synergies in replicon inhibition and a reduced frequency of resistance together lend strong support to the utility of combinations of DAAs for the treatment of HCV, and the identification of altered resistance profiles during combination treatment provides useful information for monitoring resistance in the clinic.

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Wang, Chunfu, Lourdes Valera, Lingling Jia, Melissa J. Kirk, Min Gao et Robert A. Fridell. « In VitroActivity of Daclatasvir on Hepatitis C Virus Genotype 3 NS5A ». Antimicrobial Agents and Chemotherapy 57, n^o 1 (22 octobre 2012) : 611–13. http://dx.doi.org/10.1128/aac.01874-12.

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ABSTRACTThe NS5A replication complex inhibitor daclatasvir (DCV; BMS-790052) inhibits hybrid replicons containing hepatitis C virus (HCV) genotype 3a (HCV3a) NS5A genes with 50% effective concentrations (EC50s) ranging from 120 to 870 pM. Selection studies with a hybrid HCV3a replicon identified NS5A residues 31 and 93 as sites for DCV-selected resistance. Our results support the potential use of DCV as a component in combination therapies for HCV3a chronic infection.

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Liu, Dandan, Juan Ji, Tanya P. Ndongwe, Eleftherios Michailidis, Charles M. Rice, Robert Ralston et Stefan G. Sarafianos. « Fast Hepatitis C Virus RNA Elimination and NS5A Redistribution by NS5A Inhibitors Studied by a Multiplex Assay Approach ». Antimicrobial Agents and Chemotherapy 59, n^o 6 (6 avril 2015) : 3482–92. http://dx.doi.org/10.1128/aac.00223-15.

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ABSTRACTWhile earlier therapeutic strategies for the treatment of hepatitis C virus (HCV) infection relied exclusively on interferon (IFN) and ribavirin (RBV), four direct-acting antiviral agents (DAAs) have now been approved, aiming for an interferon-free strategy with a short treatment duration and fewer side effects. To facilitate studies on the mechanism of action (MOA) and efficacy of DAAs, we established a multiplex assay approach, which employs flow cytometry, aGaussialuciferase reporter system, Western blot analysis, reverse transcription-quantitative PCR (RT-qPCR), a limited dilution assay (50% tissue culture infectious dose [TCID50]), and an image profiling assay that follows the NS5A redistribution in response to drug treatment. We used this approach to compare the relative potency of various DAAs and the kinetics of their antiviral effects as a potential preclinical measure of their potential clinical utility. We evaluated the NS5A inhibitors ledipasvir (LDV) and daclatasvir (DCV), the NS3/4A inhibitor danoprevir (DNV), and the NS5B inhibitor sofosbuvir (SOF). In terms of kinetics, our data demonstrate that the NS5A inhibitor LDV, followed closely by DCV, has the fastest effect on suppression of viral proteins and RNA and on redistribution of NS5A. In terms of MOA, LDV has a more pronounced effect than DCV on the viral replication, assembly, and infectivity of released virus. Our approach can be used to facilitate the study of the biological processes involved in HCV replication and help identify optimal drug combinations.

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Hikita, Hayato, et Tetsuo Takehara. « NS5A-P32 Deletion in Hepatitis C Genotype 1b Infection is the Most Refractory Treatment-Mediated Amino Acid Change Exhibiting Resistance to all NS5A Inhibitors ». Seminars in Liver Disease 40, n^o 02 (13 décembre 2019) : 143–53. http://dx.doi.org/10.1055/s-0039-3402001.

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AbstractNS5A-P32 deletion (P32del) is a resistance-associated amino acid change that has recently gained popularity in direct-acting antiviral treatment for chronic hepatitis C. Although not yet detected in naive patients, it appears in 5 to 10% of hepatitis C genotype 1b patients who fail to respond to daclatasvir/asunaprevir and sofosbuvir/ledipasvir treatments. In contrast to signature resistance-associated substitutions, such as substitutions at the NS5A-L31 and NS5A-Y93 positions, it shows complete resistance to all NS5A inhibitors in replicon and cell culture. Studies of humanized liver mice suggest that P32del retains good replication fitness and requires two classes of antivirals, except NS5A inhibitors, to be suppressed effectively. Patients with the P32del virus do not respond to glecaprevir/pibrentasvir but do respond to sofosbuvir/velpatasvir/voxilaprevir, presumably to sofosbuvir + glecaprevir/pibrentasvir, and at least partially to sofosbuvir/velpatasvir + ribavirin. Attention should be given to P32del in patients who experience failure with any NS5A inhibitor, especially those with genotype 1b infection.

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O'Boyle, Donald R., Peter T. Nower, Min Gao, Robert Fridell, Chunfu Wang, Piyasena Hewawasam, Omar Lopez et al. « Synergistic Activity of Combined NS5A Inhibitors ». Antimicrobial Agents and Chemotherapy 60, n^o 3 (28 décembre 2015) : 1573–83. http://dx.doi.org/10.1128/aac.02639-15.

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Daclatasvir (DCV) is a first-in-class hepatitis C virus (HCV) nonstructural 5A replication complex inhibitor (NS5A RCI) that is clinically effective in interferon-free combinations with direct-acting antivirals (DAAs) targeting alternate HCV proteins. Recently, we reported NS5A RCI combinations that enhance HCV inhibitory potentialin vitro, defining a new class of HCV inhibitors termed NS5A synergists (J. Sun, D. R. O’Boyle II, R. A. Fridell, D. R. Langley, C. Wang, S. Roberts, P. Nower, B. M. Johnson F. Moulin, M. J. Nophsker, Y. Wang, M. Liu, K. Rigat, Y. Tu, P. Hewawasam, J. Kadow, N. A. Meanwell, M. Cockett, J. A. Lemm, M. Kramer, M. Belema, and M. Gao, Nature 527:245–248, 2015, doi:10.1038/nature15711). To extend the characterization of NS5A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a, and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV and NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multilog drop in HCV, followed by rebound due to the emergence of resistance. DCV–NS5A-Syn combinations were highly efficient at clearing cells of viruses, in line with the trend seen in replicon studies. The retreatment of resistant viruses that emerged using DCV monotherapy with DCV–NS5A-Syn resulted in a multilog drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on wild-type (WT) virus. A triple combination of DCV, NS5A-Syn, and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV and NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy and tools for explorations of NS5A function.

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Yau, Alan Hoi Lun, et Eric M. Yoshida. « Hepatitis C Drugs : The End of the Pegylated Interferon Era and the Emergence of All-Oral, Interferon-Free Antiviral Regimens : A Concise Review ». Canadian Journal of Gastroenterology and Hepatology 28, n^o 8 (2014) : 445–51. http://dx.doi.org/10.1155/2014/549624.

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Between 2001 and 2011, the standard of care for chronic hepatitis C virus (HCV) infection was a combination of pegylated interferon (PEGIFN) and ribavirin (RBV). In May 2011, boceprevir and telaprevir, two first-generation NS3/4A protease inhibitors, were approved in combination with PEG-IFN and RBV for 24 to 48 weeks in hepatitis C virus genotype 1 infections. In December 2013, simeprevir, a second-generation NS3/4A protease inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotype 1, while sofosbuvir, a NS5B nucleotide polymerase inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotypes 1 and 4, as well as with RBV alone for 12 weeks in genotype 2 and for 24 weeks in genotype 3. Sofosbuvir combined with simeprevir or an NS5A replication complex inhibitor (ledipasvir or daclatasvir) with or without RBV for 12 weeks in genotype 1 resulted in a sustained virological response >90%, irrespective of previous treatment history or presence of cirrhosis. Similarly impressive sustained virological response rates have been shown with ABT-450/r (ritonavir-boosted NS3/4A protease inhibitor)-based regimens in combination with other direct-acting antiviral agent(s) with or without RBV for 12 weeks in genotype 1. The optimal all-oral interferon-free antiviral regimen likely entails a combination of an NS5B nucleotide polymerase inhibitor with either a second-generation NS3/4A protease inhibitor or an NS5A replication complex inhibitor with or without RBV. Further research is needed to determine the role of resistance testing, clarify the optimal follow-up duration post-treatment, and evaluate the antiviral efficacy and safety in difficult-to-cure patient populations.

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Friborg, Jacques, Steven Levine, Chaoqun Chen, Amy K. Sheaffer, Susan Chaniewski, Stacey Voss, Julie A. Lemm et Fiona McPhee. « Combinations of Lambda Interferon with Direct-Acting Antiviral Agents Are Highly Efficient in Suppressing Hepatitis C Virus Replication ». Antimicrobial Agents and Chemotherapy 57, n^o 3 (28 décembre 2012) : 1312–22. http://dx.doi.org/10.1128/aac.02239-12.

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ABSTRACTThe clinical efficacy of a pegylated form of human lambda 1 interferon (IFN-λ1; also referred to herein as lambda) has been demonstrated in patients chronically infected with hepatitis C virus (HCV) representing genotypes 1 through 4. In these proof-of-concept studies, lambda showed an improved safety profile compared to the pegylated form of alfa interferon (referred to herein as alfa). In the study described in this report, an assessment of thein vitroantiviral activity of type III IFNs toward different HCV replicons revealed that the unpegylated recombinant form of IFN-λ1 (rIFN-λ1) exerted the most robust effect, while rIFN-λ3 exhibited greater activity than rIFN-λ2. More importantly, cross-resistance to rIFN-λ1 was not observed in replicon cell lines known to have reduced susceptibility to investigational direct-acting antiviral (DAA) agents targeting the essential HCV nonstructural protein NS3, NS5A, or NS5B. When combined with either rIFN-α, the NS3 protease inhibitor (NS3 PI) asunaprevir (ASV), the NS5A replication complex inhibitor (NS5A RCI) daclatasvir (DCV), or the NS5B polymerase site I inhibitor (NS5B I) BMS-791325, rIFN-λ1 displayed a mixture of additive and synergistic effects. In three-drug combination studies, inclusion of lambda with ASV and DCV also yielded additive to synergistic effects. In line with these observations, it was demonstrated that a regimen that used a combination of rIFN-λ1 with one or two DAAs was superior to an IFN-free regimen in clearing HCV RNA in genotype 1a cell lines representing wild-type and NS3 protease inhibitor-resistant sequences. Overall, these data support further clinical development of lambda as part of alternative combination treatments with DAAs for patients chronically infected with HCV.

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McPhee, Fiona, Amy K. Sheaffer, Jacques Friborg, Dennis Hernandez, Paul Falk, Guangzhi Zhai, Steven Levine et al. « Preclinical Profile and Characterization of the Hepatitis C Virus NS3 Protease Inhibitor Asunaprevir (BMS-650032) ». Antimicrobial Agents and Chemotherapy 56, n^o 10 (6 août 2012) : 5387–96. http://dx.doi.org/10.1128/aac.01186-12.

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ABSTRACTAsunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor daclatasvir. ASV competitively binds to the NS3/4A protease complex, withKivalues of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC50s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC50, 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC50, >12 μM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposuresin vivoin several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the inhibitor EC50s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility in a combination with other anti-HCV agents in the treatment of HCV-infected patients.

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Plaza, Zulema, Vincent Soriano, Eugenia Vispo, Maria del Mar Gonzalez, Pablo Barreiro, Eduardo Seclén et Eva Poveda. « Prevalence of natural polymorphisms at the HCV NS5A gene associated with resistance to daclatasvir, an NS5A inhibitor ». Antiviral Therapy 17, n^o 5 (2012) : 921–26. http://dx.doi.org/10.3851/imp2091.

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Thèses sur le sujet "Daclatasvir, NS5A inhibitor"

REGHELLIN, VERONICA. « Studies on the mechanism of action of antiviral agents targeting the replication complex of hepatitis c virus ». Doctoral thesis, Università degli Studi di Milano-Bicocca, 2014. http://hdl.handle.net/10281/52708.

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At the moment, several companies are studying the clinical potential of different all-oral combinations of direct-acting antivirals in ongoing studies. The most promising interferon-free combination therapies that are on the horizon include linear or cyclic NS3/4A protease inhibitors, nucleoside as well as non-nucleoside NS5B polymerase inhibitors , and NS5A inhibitors. DAAs that target NS3/4A (protease) and NS5B (RNA-dependent RNA polymerase) inhibit the enzymatic activity of these proteins. NS5A replication complex inhibitors will likely form a component of future interferon-free drug regimens but despite their remarkable potential to treat chronic hepatitis C, the detailed mechanism of action for this class of drug remains unclear. The goal of my work was to investigate the mechanism of action of different classes of antiviral agents believed to target the NS5A protein in the replication complex in order to improve the possibility to translate basic knowledge to a more meaningful clinical application. More specifically I focused my research on two classes of compounds, characterized by distinct resistance patterns in NS5A: a first class – with examples at the final stages of clinical development, represented by Daclatasvir (Lemm et al., 2011), and a second class - at earlier stages of development - represented by anilino-quinazolines such as A-831/AZD-2836 (Quinkert et al., 2008). I contributed to demonstrate that both of these inhibitor classes, by binding respectively to either HCV NS5A or to an NS5A-associated protein, PI4KIIIα, eventually interfere with the accumulation of PI4P 98 and cholesterol in the HCV replication membranous compartment, thus abrogating the ability of the virus form to replicate its RNA genome.

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Grimm, Christian [Verfasser], Robert [Gutachter] Tampé et Christoph [Gutachter] Welsch. « Charakterisierung des Lipidbindungsverhaltens und der Proteinfaltung von HCV NS5A unter Einfluss des NS5A-Inhibitors Daclatasvir / Christian Grimm ; Gutachter : Robert Tampé, Christoph Welsch ». Frankfurt am Main : Universitätsbibliothek Johann Christian Senckenberg, 2021. http://d-nb.info/1239730276/34.

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Chapitres de livres sur le sujet "Daclatasvir, NS5A inhibitor"

Belema, Makonen, Shawn K. Pack et Nicholas A. Meanwell. « Daclatasvir (Daklinza) : The First-in-Class HCV NS5A Replication Complex Inhibitor ». Dans Innovative Drug Synthesis, 43–60. Hoboken, NJ, USA : John Wiley & Sons, Inc, 2015. http://dx.doi.org/10.1002/9781118819951.ch3.

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Meanwell, Nicholas A., et Makonen Belema. « The Discovery and Development of Daclatasvir : An Inhibitor of the Hepatitis C Virus NS5A Replication Complex ». Dans Topics in Medicinal Chemistry, 27–55. Cham : Springer International Publishing, 2019. http://dx.doi.org/10.1007/7355_2018_47.

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Belema, Makonen, Steven M. Schnittman et Nicholas A. Meanwell. « Case History : The Discovery of the First Hepatitis C Virus NS5A Replication Complex Inhibitor Daclatasvir (Daklinza™) ». Dans Medicinal Chemistry Reviews, 375–97. Medicinal Chemistry Division of the American Chemical Society, 2016. http://dx.doi.org/10.29200/acsmedchemrev-v51.ch22.

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